Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines
Antitumor effect of adenovirus-mediated p53 family gene transfer on osteosarcoma cell lines
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DOI：
10.4161/cbt.6.7.4320
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发表时间：
2007-07
影响因子：
3.6
通讯作者：
Yuichiro Oshima;Y. Sasaki;H. Negishi;M. Idogawa;M. Toyota;T. Yamashita;T. Wada;S. Nagoya;Satoshi Satoshi-Satoshi;T. Yamashita;T. Tokino
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文献类型：
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作者：
Yuichiro Oshima;Y. Sasaki;H. Negishi;M. Idogawa;M. Toyota;T. Yamashita;T. Wada;S. Nagoya;Satoshi Satoshi-Satoshi;T. Yamashita;T. Tokino
骨肉瘤（OS）是最常见的骨恶性肿瘤之一。虽然在过去几年中，由于化疗和放疗方案的强化，OS的预后有了显著改善，但对于复发和不能手术的病例，需要新的治疗方法。P73和p63，像它们的同系物，肿瘤抑制因子p53一样，能够诱导几种细胞类型的凋亡。在这里，我们评估了p73和p63对11种不同的人类OS细胞系的抗肿瘤作用。在体外，腺病毒介导的p63γ转导诱导了对p53介导的凋亡具有抗性的OS细胞的凋亡，而p73α或p63α转导后观察到的影响较小。有趣的是，在携带mdm2扩增的OS细胞中，p63γ的凋亡作用大于野生型p53。随后，我们测定了瘤内注射表达p53家族成员的腺病毒载体对裸鼠移植的Saos-2细胞的异种移植物的体内治疗效果，结果表明，与p53相比，p63γ感染可显著抑制肿瘤生长。此外，外源性p73β和p63γ显著增加了OS细胞对阿霉素和顺铂的化疗敏感性，这两种化疗药物通常用于治疗OS。我们的研究结果表明，腺病毒介导的p53家族成员的转导可能在OS的基因治疗中具有实用价值，特别是在与化疗药物联合使用时。
Osteosarcoma (OS) is one of the most common malignancies of the bone. Although prognosis of OS has improved significantly during the past several years due to more intensive chemotherapy and radiotherapy regimens, new therapeutic approaches are needed for recurrent and inoperable cases. p73 and p63, like their homologue, the tumor suppressor p53, are able to induce apoptosis in several cell types. Here, we evaluated the antitumor effects of p73 and p63 on eleven different human OS cell lines. In vitro, adenovirus-mediated transduction of p63γ induced apoptosis in OS cells that are resistant to p53-mediated apoptosis, while less effect was observed following transduction of p73α or p63α. Interestingly, the apoptotic effects of p63γ were greater than those of wild-type p53 in OS cells carrying MDM2-amplification. We then determined the in vivo therapeutic effect of intratumoral injection of adenovirus-vector expressing p53 family members on xenografts derived from Saos-2 cells implanted in nude mice, and showed that infection with p63γ significantly suppressed tumor growth compared with p53. In addition, exogenous p73β and p63γ significantly increased the chemosensitivity of OS cells to doxorubicin and cisplatin, chemotherapeutic agents commonly used in the treatment of OS. Our results suggest that adenovirus-mediated transduction of p53 family members may have utility in gene therapy for OS, particularly in combination with chemotherapeutic agents.